Platelet activation and COVID-19 mortality: Insights from coagulopathy, antiplatelet therapy and inflammation

ABSTRACT

Background: Severe coronavirus disease 2019 (COVID-19) is associated with inflammatory cytokine burst and coagulopathy. Platelets may contribute to microthrombosis development and be a target in COVID-19 therapy. Aim(s) To determine the significance of platelet activation and antiplatelet agents (APAs) treatment in COVID-19 pathophysiology and mortality in two cohorts of patients with COVID-19. Method(s) We explored two cohorts of COVID-19 patients Cohort A (NCT04624997) included 208 ambulatory and hospitalized patients of different clinical severity with evaluation of soluble CD40 ligand (sCD40L) and P-selectin (sP-sel) plasma levels of within the first 48 hours following admission. Cohort B included 2878 patients initially admitted in medical ward with collection of clinical characteristics and outcomes (NCT04344327). In both cohorts, the primary outcome was in-hospital mortality. Result(s) In cohort A, circulating median levels of sCD40L and sP-sel were significantly increased solely in critical patients with COVID-19 (sP-sel 40059 pg/ml, IQR 26876-54678;sCD40L 1914 pg/ml IQR 1410-2367;p < 0.001 for both), signaling platelet hyper-activation. However, pre-hospitalization APAs did not significantly modified sCD40L and sP-sel levels. Admission sP-sel levels were predictive in-hospital mortality (Kaplan-Meier log-rank p = 0.004), even after adjustment on CRP, while adjustment on D-dimer abolished this relationship, suggesting that platelet activation is highly interrelated with coagulopathy. We confirmed this finding in a Cox model adjusted for age, sex, CRP and D-dimer levels (Odds ratio 1.78, 95% CI 0.63-4.50). We confirmed in cohort B (2878 patients) that, among patients receiving APA before hospitalization, there was no significant difference in the proportion of death in a Cox model (Hazard ratio 1.0, IQR0.77-1.30) adjusted for demographic comorbidities. Conclusion(s) Our findings highlight the critical role of coagulopathy, in contrast to platelet activation, in discriminating COVID-19 severity and increased risk of in-hospital mortality. We also confirm that APAs before hospitalization do not influence neither mortality nor platelet activation. (Table Presented).